1. Field of the Invention
The present invention relates to a topical composition for the skin (hereinafter may be simply referred to as a topical skin composition) exhibiting effects of retarding aging of the skin or rejuvenating the skin and of suppressing hair growth.
2. Background Art
Studies have revealed that aging of the skin is mainly caused by advancing age, drying, oxidation, or sunlight (i.e., UV rays). Aging of the skin is recognized by a decrease in collagen or elastin in the dermis of the skin; a decrease in mucopolysaccharides, including hyaluronic acid; or the presence of cells which are damaged by UV rays.
For the prevention of wrinkle formation, however, sufficient effects have not yet been attained, for example, by a collagen-containing cosmetic composition. In addition, a number of research projects have focused on skin aging caused by exposure to UV rays. However, cosmetic compositions superseding UV absorbing agents or UV protecting agents have not yet been developed.
There is a trend towards a preference for hairless bodies, particularly, hairless arms or legs, for reasons of aesthetic appearance. Various methods have been tried in the pursuit of body hair removal, for example, a mechanical hair-removal method making use of a shaver or hair-tweezers, a method for removing body hair from the hair root by use of a hair removing agent, and a method for removing body hair through chemical action of a hair removing agent.
However, the aforementioned hair removing methods physically or chemically stimulate the skin, and are limited by the unsatisfactory duration of the hairless state. Therefore, there is a need for the development of a method which facilitates removal of body hair.
In view of the foregoing, an object of the present invention is to provide a topical composition for the skin exhibiting effects with respect to retarding aging of the skin, such as wrinkle formation, or rejuvenating the skin, and of suppressing hair growth.
The present inventors have found that a dipeptide compound having a specific structure or a salt thereof exhibits excellent effects with respect to suppressing wrinkle formation, preventing a reduction in skin elasticity, and suppressing hair growth, and that the compound or the salt is effectively employed in a topical skin composition for retarding aging of the skin or suppressing hair growth.
Accordingly, the present invention provides a topical skin composition comprising a dipeptide compound represented by formula (1) or a salt of the dipeptide: 
wherein R1 represents a hydrogen atom, an alkyl group, an alkanoyl group, or xe2x80x94CH(R6)COOR7 (wherein R6 represents a hydrogen atom or a lower alkyl group, and R7 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or an aralkyl group);
R2 represents a hydrogen atom or an alkyl group which may have a substituent;
R3 represents a lower alkyl group or a phenyl group;
R4 represents a hydrogen atom or a lower alkyl group, and may form a heterocyclic ring together with R5 and an adjacent nitrogen atom;
R5 represents a hydrogen atom, an alkyl group which may have a substituent, or an aralkyl group which may have a substituent, and may form the heterocyclic ring together with R4;
X represents xe2x80x94COOR8 (wherein R8 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or an aralkyl group) or xe2x80x94SO3H; and
n is an integer of 0-4; and a pharmaceutically acceptable carrier therefor.
The present invention also provides, as a novel compound which has not yet been described in any literature, N-(carboxymethyl)phenylalanyl-xcex2-alanine, among dipeptide compounds represented by formula (1), or a salt thereof.
Various other objects, features and many of the attendant advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description of the preferred embodiments.
In formula (1), an alkyl group represented by R1 is preferably a C1-C6 alkyl group, may be a linear or branched alkyl group, and is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a t-butyl group.
An alkanoyl group represented by R1 is preferably a C1-C6 alkanoyl group, may,be a linear or branched alkanoyl group, and is more preferably an acetyl group, a propionyl group, or a butyryl group.
A lower alkyl group represented by R3, R4, R6, R7, or R8 is preferably a C1-C6 alkyl group, may be a linear or branched alkyl group, and is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a t-butyl group.
A lower alkenyl group represented by R7 or R8 is preferably a C2-C6 alkenyl group, more preferably a vinyl group or a propenyl group.
An aralkyl group represented by R7 or R8 is a C7-C18 aralkyl group. Specific examples include a phenyl C1-C6 alkyl group, a biphenyl C1-C6 alkyl group, and a naphthyl C1-C6 alkyl group. Of these, a phenyl C1-C6 alkyl group is preferable, and a benzyl group is more preferable.
An alkyl group which may have a substituent, represented by R2, may be a C1-C6 alkyl group, a carboxy C1-C6 alkyl group, or a C1-C6 alkoxycarbonyl C1-C6 alkyl group. Of these, a C1-C6 alkyl group is preferable. R2 is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, or a t-butyl group.
An alkyl group which may have a substituent, represented by R5, may be a C1-C6 alkyl group, a carboxy C1-C6 alkyl group, or a C1-C6 alkoxycarbonyl C1-C6 alkyl group. Of these, a C1-C6 alkyl group and a carboxy C1-C6 alkyl group are preferable. R5 is more preferably a methyl group, an isopropyl group, an isobutyl group, a t-butyl group, a carboxymethyl group, or a carboxyethyl group.
A heterocyclic ring which is formed by R4 and R5 may be pyrrolidine or piperidine.
An integer n is preferably 0, 1, or 2.
In formula (1), R1 is more preferably a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkanoyl group, or xe2x80x94CH(R6)COOR7 (wherein R6 represents a hydrogen atom or a C1-C6 alkyl group, and R7 represents a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a phenyl C1-C6 alkyl group). R2 is more preferably a hydrogen atom or a C1-C6 alkyl group. R3 is more preferably a C1-C6 alkyl group or a phenyl group. R4 is more preferably a hydrogen atom or a C1-C6 alkyl group. R5 is more preferably a hydrogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group, or a carboxy C1-C6 alkyl group. X is more preferably xe2x80x94COOR8 (wherein R8 represents a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a phenyl C1-C6 alkyl group) or xe2x80x94SO3H. An integer n is more preferably 0, 1, or 2.
Examples of salts of a dipeptide compound (1) include alkali metal salts, alkaline earth metal salts, amine salts, amino acid salts, and acid addition salts. Of these, alkali metal salts and amino acid salts are preferable. A dipeptide compound (1) may have optical activity, and its steric configuration may be any of R, S, and a racemic mixture. The compound may also be in the form of a hydrate.
Among dipeptide compounds of formula (1), the more preferred compounds are as follows: 
Phe-Gly (compound 11); Phe-xcex2-Ala (compound 12); Phe-Phe (compound 13); Phe-Leu (compound 14); Phe-Ala (compound 15); and Phe-Asp (compound 16): Phe-Tau (compound 17).
Of these, compound 1 and compound 12 are more preferable.
A compound of formula (1) in which R1 is a hydrogen atom may be synthesized through a process described in xe2x80x9cK. Ienalga, K. Higashihara, and H. Kimura, Chem. Pharm. Bull., 35, 1249-1254 (1987).xe2x80x9d A compound of formula (1) in which R1 is not a hydrogen atom but is any of the aforementioned groups may be synthesized through, for example, the following process: 
(wherein Y represents a halogen atom, a p-toluenesulfonyl group, or a methanesulfonyloxy group; R1 represents any of the aforementioned groups other than a hydrogen atom; and R2 through R5, n, and X are the same as described above).
Namely, a compound (2) is reacted with a compound (3) in the presence or absence of a base, and if necessary, hydrolysis by use of a base such as sodium hydroxide, or catalytic hydrogenation by use of a catalyst such as palladium carbon may be: carried out, to thereby yield a compound (1) of the present invention.
Examples of bases which may be employed in the reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, and triethylamine. Of these, potassium carbonate and triethylamine are preferable, and triethylamine is more preferable.
Examples of solvents which may be employed in the reaction include water, dimethylformamide, tetrahydrofuran, benzene, toluene, xylene, and hexane. Of these, toluene and benzene are preferable, and toluene is more preferable. The reaction temperature is xe2x88x9230 to 200xc2x0 C., preferably 10 to 90xc2x0 C., more preferably 40 to 70xc2x0 C.
A dipeptide compound (1) or a salt thereof is incorporated into the topical skin composition of the present invention in an amount of 0.0001-40 wt. % (hereinafter xe2x80x9cwt. %xe2x80x9d will be simply referred to as xe2x80x9c%xe2x80x9d), preferably 0.01-20%.
The topical skin composition of the present invention is more preferably used for preventing and ameliorating unfavorable skin conditions caused by aging of the skin, such as wrinkles, flabbiness, and reduction of elasticity; or for suppressing hair growth.
The topical skin composition of the present invention may further contain a keratinization-ameliorating agent, to thereby enhance the effect of retarding aging of the skin, such as wrinkle formation, or the effect of suppressing hair growth. Examples of such keratinization-ameliorating agents include sphingosine derivatives.
The topical skin composition of the present invention may appropriately contain, in addition to the aforementioned ingredients, a variety,of ingredients or carriers which are usually employed in cosmetics, quasidrugs, and drugs. Examples of such ingredients or carriers include humectants, powders, gelation agents, thickeners, surfactants, emulsifiers, anti-inflammatory agents, antioxidants, pH regulating agents, chelating agents, preservatives, dyes, perfumes, UV absorbing-agents, UV protecting agents, existing skin-aging preventive or retarding agents such as collagen, and existing hair-growth suppressing agents. The composition may be produced through a conventional method in accordance with the application form.
The topical skin composition of the present invention may be used as a skin composition for pharmaceutical use or a cosmetic composition. Examples of pharmaceutical compositions include a-variety of ointments containing a pharmaceutically active ingredient. Such an ointment may comprise an oily base, or an oil-in-water or water-in-oil emulsion base. No particular limitation is imposed on the species of oily base, and, for example, vegetable oil, animal oil, synthetic oil, fatty acid, or natural or synthetic glyceride may be employed. No particular limitation is imposed on the species of pharmaceutically active ingredient, and, for example, analgesic and anti-inflammatory agents, antipruritic drugs, astringent agents, or hormones may be appropriately employed in accordance with needs.
Examples of cosmetic compositions include lotions, emulsions, creams, ointments, sticks, solutions in organic solvents or purified water, packs, gels-and aerosols. Namely, the cosmetic composition may be employed as a lotion, an oil essence, an O/W-type or, W/O-type cream, a pack, a foundation, a skin-cleansing agent, a tonic, a bathing agent, or an aerosol.